Abstract
Histone lysine methylation is a central modification to mark functionally distinct chromatin regions. In particular, H3-K9 trimethylation has emerged as a hallmark of pericentric heterochromatin in mammals. Here we show that H4-K20 trimethylation is also focally enriched at pericentric heterochromatin. Intriguingly, H3-K9 trimethylation by the Suv39h HMTases is required for the induction of H4-K20 trimethylation, although the H4 Lys 20 position is not an intrinsic substrate for these enzymes. By using a candidate approach, we identified Suv4-20h1 and Suv4-20h2 as two novel SET domain HMTases that localize to pericentric heterochromatin and specifically act as nucleosomal H4-K20 trimethylating enzymes. Interaction of the Suv4-20h enzymes with HP1 isoforms suggests a sequential mechanism to establish H3-K9 and H4-K20 trimethylation at pericentric heterochromatin. Heterochromatic H4-K20 trimethylation is evolutionarily conserved, and in Drosophila, the Suv4-20 homolog is a novel PEV modifier to regulate position-effect variegation. Together, our data indicate a function for H4-K20 trimethylation in gene silencing and further suggest H3-K9 and H4-K20 trimethylation as important components of a repressive pathway that can index pericentric heterochromatin.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cells, Cultured
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Chromobox Protein Homolog 5
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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Conserved Sequence
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Drosophila / genetics
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Female
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Fibroblasts
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Gene Silencing
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Genes, Suppressor
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Heterochromatin / genetics
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Heterochromatin / metabolism*
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / immunology
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Histones / metabolism*
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Lysine / metabolism
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Mammals
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Methylation*
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Methyltransferases / genetics
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Methyltransferases / metabolism
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Mice
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Molecular Sequence Data
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Protein Methyltransferases
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Protein Structure, Tertiary
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Substrate Specificity
Substances
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Chromosomal Proteins, Non-Histone
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Drosophila Proteins
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Heterochromatin
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Histones
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Repressor Proteins
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Chromobox Protein Homolog 5
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Suv39h1 protein, mouse
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Histone Methyltransferases
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Hmt4-20 protein, Drosophila
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Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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Lysine
Associated data
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GENBANK/AY555192
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GENBANK/AY555193